This proposal is a multicenter planning grant toward a future comparative effectiveness research (CER) project aimed at improving the iron burden of transfusion-dependent thalassemia patients. Worldwide, the standard of care for (non-transplanted) thalassemia major patients is ongoing transfusion therapy plus lifelong iron chelation. This therapy has improved lifespan in thalassemia over the last three decades, but chelation adequacy is variable, and the leading cause of death remains cardiac iron overload. Iron measurements by MRI have simplified assessment of total-body and cardiac iron burden, yet chelation status of many patients is suboptimal. Many factors affect adequacy of chelation, including transfusion burden and adherence. Choice of chelator(s) and dose regimen(s) are also vital factors, but the optimal strategy is unclear presently. This lack of knowledge is not amenable to randomized clinical trials for many reasons, e.g. (a) unwillingness of patients to be randomized to parenteral therapy when oral chelators are available, (b) varying regulatory approval status of the chelators in different countries, and (c) logistical, financial and corporate impediments for supporting randomized combination therapy approaches between and/or among chelator brands. The working hypothesis for this proposal is that the Thalassemia Longitudinal Cohort (TLC), an ongoing NHLBI-funded project which captures chelator regimens, iron status, transfusion burden, and measures of adherence and end-organ function for ~400 patients, can form the framework of an observational study that will underlie the planned CER study at TLC sites in the US, Canada, the UK and a new planned site in Thailand. The project will be accomplished in two specific aims: Aim 1 is to develop the framework and infrastructure for a multicenter, international CER study of iron chelation in thalassemia major. Aim 2 is to provide both feasibility information and exploratory analyses of chelator strategies for the planned R01 application. Feedback from initial analyses in aim 2 will be used iteratively to improve Aim 1 logistics in anticipation of an R01 application in 2012.